Perturbations in protein quality control have been implicated in many age-related neurodegenerative diseases, which are typically characterized by the accumulation of aggregated proteins such as tau and ?-synuclein. Recent studies have shown that ubiquilin-2 (UBQLN2), a protein quality control protein, co-localizes with protein aggregates in Alzheimer?s disease and related dementias (ADRD), including Lewy body dementia and Parkinson?s disease dementia, suggesting that UBQLN2 is implicated in these disorders. UBQLN2 acts as a shuttle for ubiquitin-dependent clearance of substrate proteins by the proteasome. The four-member family of ubiquilin proteins, including UBQLN2, contain N-terminal ubiquitin-like (UBL) and C-terminal ubiquitin-associated (UBA) domains that allow ubiquitinated substrates to be shuttled to the proteasome for degradation. Ubiquilins may also target proteins for degradation by autophagy, although this is not well-established in the literature. This proposal will build on recent models and reagents developed in our laboratory to explore the role of UBQLN2 in synucleinopathies, such as Lewy body dementia and Parkinson?s disease dementia. Several studies have shown that UBQLN2 co-localizes with ?-synuclein aggregates in disease, but it is unknown whether UBQLN2 normally plays a role in handling ?-synuclein or the other prominent proteins underlying common age-related neurodegenerative diseases. Preliminary studies have shown that UBQLN2 overexpression markedly reduces ?-synuclein levels, while UBQLN2 knockdown increases ?-synuclein levels. In two aims, this proposal will define the role of UBQLN2 in clearing alpha-synuclein, both normally and in disease states. The first aim will use cellular models to investigate the mechanism by which UBQLN2 regulates ?-synuclein. We will use domain deletion mutants to investigate the role of ubiquitin, chaperone, and proteasome binding domains on UBQLN2 in clearing ?-synuclein. Aim 2 will use mouse models to investigate the role of UBQLN2 in clearing ?-synuclein in vivo. Additionally, this aim will determine if UBQLN2-mediated clearance ameliorates ?-synuclein pathology. The proposed study will lead to a better understanding of protein quality control as it pertains to neurodegenerative disease and potentially reveal novel therapeutic targets for ADRD.